Use of lipids as adjuvents in the production of solid medicinal forms by the melt extrusion process

ABSTRACT

Lipids are used as aids in the production of solid drug forms by melt extrusion.

This application is a 371 of PCT/EP96/103/667 filed Aug. 21, 1996.

The present invention relates to the use of lipids as aids in theproduction of solid drug forms by melt extrusion.

The production of solid drug forms by melt extrusion is disclosed, forexample, in U.S. Pat. No. 4,880,585, wherein the drug form is producedfrom the melt, which contains active ingredient and is still plastic,with the aid of a molding calender which directly molds tablets from themelt.

It has long been known that, in almost all cases when tablets are madefrom granules, satisfactory results are achieved only if a small amountof a lubricant is added to the formulations, after the granulation butbefore the tabletting, and this is deposited as a fine film on theoutsides of the granule particles and thus prevents adhesion of thegranules to the tabletting punches. The effect of these lubricants isvery great although it is necessary to add only very small amounts tothe granules (generally about 0.1 to 1% by weight; cf. H. Sucker, P.Fuchs. P. Speiser: Pharmazeutische Technologie; Georg Thieme Verlag,Stuttgart (1991), pages 259-260).

Known mold release agents for conventional processes are, for example,fatty acid esters or fatty acid salts, with only magnesium stearatenormally being used in practice. Magnesium stearate is normally added tothe granules which contain active ingredient and are ready beforetabletting.

In the production of drug forms by melt extrusion in conjunction with atabletting process such as calendering, it is crucial that the melt doesnot adhere to the surfaces of the calender rolls because, otherwise,there is no release from the molds. It also has to be taken into accountin calendering to produce tablets that the compression process in thecalender results in tablets which have a typical fin which is formed atthe interface of the pairs of molding rolls which are in contact only atthe surface. Following the calendering, this fin must be removedmechanically, generally after cooling/hardening of the melt tablets, inorder to provide the tablets with a homogeneous surface structure. Thesuccess of this deflashing depends crucially on the consistency of thecooled melt containing active ingredient. This means that despite thecalendering being satisfactory (no adhesion of the melt in thecalender), deflashing of the resulting tablets is not necessarilypossible. Many polymers form thermoplastic melts even in the presence oflarge amounts of active ingredients and/or ancillary substances, andthese are highly flexible after cooling and can be flexed over wideranges without breakage. In these cases, removal of the fins is verydifficult and often completely impossible, although there are noproblems with the extrusion and the calendering too.

Thus, it is crucial for the use of a formulation for producing tabletsby melt extrusion/calendering that, besides the complete mixture havinggood thermoplasticity, in particular it is also possible to reduce thetendency to adhere during the calendering and control the plasticity ofthe cooled melt in order to ensure deflashing of the tablets.

Melt-processable cellulose derivatives such as hydroxypropylcelluloseare, as water-soluble polymers, very suitable for producing tablets bysolvent-free melt extrusion/calendering. It is possible by admixture ofother ancillary substances, eg. HPMC (hydroxypropylmethylcellulose)polymers which are swellable in water, to control the dissolution timesof such tablets in the gastrointestinal tract, as is disclosed, forexample, in DE-A 4226753.

However, it has now been found that, in many cases whenhydroxypropylcelluloses are used as water-soluble, thermoplastic polymercomponent, although the resulting melts can be extruded satisfactorily,they

a) in many cases showed an extreme tendency to adhere during thecalendering,

b) did not permit removal of the fin because of excessive plasticity ofthe cooled melts (containing active ingredient) in the case of thecalendered tablets, and

c) caused considerable problems in cleaning the extruders because of thegreat tendency of the melt to adhere.

It is an object of the present invention to find aids which make itpossible, especially when hydroxypropylcelluloses are used as matrixpolymers in the production of drug forms by melt extrusion, to solve theabovementioned problems.

We have found that this object is achieved by using lipids as moldrelease agents and lubricants in the production of drug forms by meltextrusion.

The lipids which are suitable according to the invention are mono-, di-and triglycerides of naturally occurring fatty acids, for exampleglycerol monostearate, glycerol distearate, glycerol tristearate,glycerol tripalmitate, glycerol trimyristate, glycerol tribehenate,glycerol palmitate stearate or glyceride mixtures occurring in naturaloils, preferably hydrogenated castor oil.

Ceramides are furthermore also suitable for this purpose.

Preferred lipids are, in particular, phospholipids, withphosphoglycerides such as lecithins being particularly preferred.Hydrogenated lecithins such as soybean and egg lecithins are veryparticularly preferred.

The lipids can be used in amounts of 0.1-10%, preferably 1-5%, of thetotal weight of the preparations containing active ingredient.

The preparations containing active ingredient can contain as matrixpolymers melt-processable polymers, for example

polyvinylpyrrolidone,

copolymers of N-vinylpyrrolidone and vinyl acetate with up to 50% byweight of vinyl acetate,

carboxyalkylcelluloses such as carboxymethylcelluloses, alkylcellulosessuch as methylcellulose,

hydroxyalkylcelluloses such as hydroxymethyl-, hydroxyethyl-,hydroxypropyl- and hydroxybutylcellulose,

hydroxyalkylcelluloses such as hydroxyethylmethyl- andhydroxypropylmethylcellulose, or mixtures thereof.

Preferred polymers are hydroxypropylcelluloses and polymers based onvinylpyrrolidone.

Suitable active ingredients are all active ingredients which do notdecompose under the conditions of melt extrusion.

The amount of the active component in the complete preparation can varywithin wide limits depending on the activity and release rate. Thus, thecontent of active ingredient can be in the range from 0.1 to 90%,preferably from 0.5 to 60%, of the total weight of the preparation. Theonly condition is that the preparation is still melt-processable.

The preparations may furthermore contain conventional pharmaceuticalancillary substances such as bulking agents, colorants, disintegrants orstabilizers in conventional amounts.

Otherwise, the components are processed in a conventional way inextruders, preferably in single or twin screw extruders at a temperaturein the range from 50 to 200° C. The shaping of the polymer melt whichcontains active ingredient and is free of solvent to give thepreparations according to the invention can take place, for example, bycalendering the extrudate and by converting the extrudate with rotatingknives into pellets which have identical volumes and have a solidifiedsurface but are still moldable, and subsequently compressing to tabletsin conventional tabletting machines.

It is possible to mix the ancillary substances into the melt or solutionof active ingredients and polymers. It is furthermore possible toincorporate the ancillary substances together with the active ingredientinto the polymer melt. In addition, mixtures of ancillary substances,the active ingredient and the polymers can be directly melted. It isgenerally customary for a physical mixture of ancillary substances,active ingredients and the polymers to be melted together.

It has been found, surprisingly, that addition of even small amounts oflipids is able to prevent adhesion of the melts containing activeingredient.

Addition of only 3% by-weight of lecithin reduces the melt adhesion ofthe extruded composition so much that the formulations can be calenderedwithout restrictions. The cleaning of the extruder to remove theotherwise viscous, highly adhesive melt residues is considerablysimplified because lecithin-containing formulas show scarcely anyadhesion to metal and can be removed en bloc from the metal parts of theextruder which are still hot after completion of the extrusion. Theplasticity of the cooled 40 melt is also beneficially affected so thatdeflashing of the tablets (removal of fins) takes place considerablybetter.

EXAMPLES 1 TO 20

All the tests were carried out in a twin screw extruder (ZSK-40 extruderfrom Werner und Pfleiderer, Stuttgart). The extruder comprised 4heatable sections, and it was possible to heat the extruder head and theslit die separately. The temperature settings are to be found in thetable. The extruded melt was discharged in the form of a strip 12-14 cmwide through a slit die and subsequently directly compressed to tabletsin a molding calender consisting of a pair of counter-rotating moldingrolls (coolable). The tablets had an elongate, rod-like shape (oblongtablets without bar). The raw materials listed in the table havepreviously been mixed in a gyro-wheel mixer and fed as mixture into theextruder via a weigh feeder delivering 20 to 30 kg/h. The extruderconveyor was operated in all cases at 100 to 150 rpm.

For comparison purposes, formulations in which no lipid was used wereprocessed. Although extrusion was possible in all these cases,calendering was not, because it was impossible to remove the tabletsfrom the pairs of molding rolls in the calender. In addition, cleaningof the parts of the extruder coming into contact with the product wasconsiderably more difficult in these cases (composition stronglyadherent to metal surfaces) than with lipid-containing formulations.

TABLE 1 Ancillary Ex. Active ingredient Polymer substance Lipid WeightNo. (a) (b) (c) (d) + (e) a:b:c:d:e T 1 T 2 T 3 T 4 T H T D  1 VerapamilHCl HPC HPMC-100 Cast. 46/29/20/5/0 80 100 100 100 100 100  2 VerapamilHCl HPC HPMC-100 Lec. 49/38/10/3/0 80 100 110 110 110 110  3 VerapamilHCl HPC HPMC-4 Lec. 48/32/18/3/0 80 100 110 110 110 110  4 Verapamil HClHPC HPMC-4 Lec. 50/37/10/3/0 80 100 110 110 110 110  5 Verapamil HCl HPCHPMC-100 Lec. + cast. 50/35/10/2.5/2.5 80 100 110 110 110 110  6Verapamil HCl HPC HPMC-100 Cast. 50/33/10/7/0 80 100 105 110 110 110  7Nifedipine HPC HPMC-100 Lec. 7.7/69.3/20/3/0 90 110 100 110 110 115  8Nifedipine HPC HPMC-100 Lec. 23.1/51.9/20/5/0 90 110 110 110 120 120  9Nifedipine HPC HPMC-100 Cast. 23.1/51.9/20/5/0 90 110 120 120 120 120 10¹⁾ HPC — — 20/80/0/0/0 140  140 140 140 140 130 11 ¹⁾ HPC — —21.9/78.1/0/0/0 140  140 140 140 140 130 12 Placebo HPC Mannitol —0/60/40/0/0 90 120 100 100 120 120 13 Placebo HPC — — 0/100/0/0/0 100 120 110 120 120 120 14 ¹⁾ HPC Mannitol Lec. 18.2/36.8/40/5/0 90 120 100100 110 110 15 Placebo HPC Mannitol Lec. 0/55/40/5/0 90 120 100 100 120120 16 ¹⁾ HPC Mannitol Lec. 9/46/40/5/0 90 120 100 100 110 110 17 ²⁾ HPCHPMC-100 — 10.4/49.6/40/0/0 130  110 110 110 110 115 18 Placebo HPCHPMC-100 Lec. 0/58/40/2/0 90 110 100 110 110 110 19 ²⁾ HPC HPMC-100 Lec.19.8/38.2/40/2/0 90 105  95 105 105 110 20 Placebo VA-64 Lactose Lec.0/55/40/5/0 80 100 110 110 120 130¹⁾3,4-Dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-yl)-methoxy-cumarin²⁾5-(N-Methylamino)-2-(1-isopropyl)-2-(3,4,5-trimethoxyphenyl)undecanonitrilehydrochloride HPC Hydroxypropylcellulose (Klucel, Hercules) VA-64Copolyvidone DAB (Kollidon VA-64, BASF) HPMC-100Hydroxypropylmethylcellulose (Methocel K 100 M, Colorcon) HPMC-4Hydroxypropylmethylcellulose (Methocel K 4 M, Colorcon) Lec.Hydrogenated soybean lecithin (from Stern) Cast. Hydrogenated castor oil(Cutina HR, Henkel) T 1 to T 4 Temperatures of extruder sections 1-4 (°C.) T H Temperature of extruder head (° C.) T D Temperature of extruderdie (° C.)

We claim:
 1. A process for producing a solid pharmaceutical compositionin tablet form by melt extrusion, which process consists essentially ofmixing an active ingredient, a water-soluble thermoplastic matrixpolymer and a lipid; heating the mixture until a solvent-free, polymermelt is formed; extruding the melt into a tabletting molding calender;allowing the melt to cool; and removing the formed solid pharmaceuticalcomposition in the form of a tablet from the molding calender; whereinthe lipid is used in amounts of 1-5% of the total weight of thecomposition and functions as a mold release agent and lubricant.
 2. Theprocess of claim 1, wherein the lipid is a phospho glycerine.
 3. Theprocess of claim 1, wherein the lipid is a lecithin.